Tyrosine kinase receptors are trans-membrane proteins involved in signal conversion. They propagate growth factor signals, which cascade to control cell proliferation, mutation, angiogenesis, apoptosis and other important features, from the surface of cellular to inner cellular. One class of such tyrosine kinase receptors, epidermal growth factor receptor (EGFR) tyrosine kinases, are over-expressed in many human tumor or cancers, including tumor or cancers of brain, lung, liver, bladder, chest, head and neck, esophagus, gastrointestinal track, breast, ovary, cervix, or thyroid.
EGFR is expressed in many types of tumor cells. After binding with its ligands including epidermal growth factor (EGF) or Transforming Growth Factor-α (TGF-α), EGFR activates tyrosine kinases in cytoplasmic domains and results in transphosphorylation of the tyrosine at EGFR hydroxyl terminal Then, EGFR controls multiple gene transcription through different signal transduction channels, thereby regulating cell proliferation, differentiation, and apoptosis. EGFR is closely related to tumor metastasis, vascular proliferation, and chemotherapy drug resistance.
Various molecular and cellular biology and clinical studies have demonstrated or proved that EGFR kinase inhibitor can block EGFR signal transductions related to cancer cell proliferation, metastasis and others responses, and thus achieve clinical anti-tumor therapeutic effects.
Two oral EGFR kinase inhibitors with similar chemical structures are Gefitinib (Iressa, AstraZeneca), approved by the U.S. FDA for advanced non-small cell lung cancer treatment in 2003, and Erlotinib Hydrochloride (Tarceva, Roche and OSI), approved by the U.S. FDA for advanced non-small cell lung cancer and pancreatic cancer treatment in 2004.
EGFR tyrosine kinase inhibitor (TKI) is a popular research field of a new generation of targeted anti-tumor drug in the world. U.S. Pat. No. 7,078,409B2 and CN130568C disclose preparation methods of Icotinib, and WO2010/003313 discloses a preparation method of Icotinib hydrochloride. However, the methods disclosed by U.S. Pat. No. 7,078,409B2 and CN130568C require use of highly toxic reagent, i.e, Chlorinating agent, such as (COCl)2 or phosphorus oxychloride. These highly toxic Chlorinating agents, especially Chlorinating agent containing phosphorus, are very difficult or costly to be completely removed in the later reactions. Therefore, the existing synthetic methods not only are very costly but also cause severe environment pollution problems, and present a significant threat to the health of producers and users. The preparation method disclosed in WO2010/003313 uses metal catalysts, which are also costly and difficult to be separated or recovered. Furthermore, any direct emission of such metal and phosphine ligand will cause severe environment pollutions.
The intermediary compounds designed by the present invention are used for preparing Icotinb or Icotinib hydrochloride. These preparation methods avoid use of high-toxic reagents, proceed in mild reaction conditions, and thus are easier, more economic, lower-toxic and safer than synthetic methods currently known in the art.